(Circulation. 2001;103:435.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats
From the Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, Homburg/Saar, Germany, and the Institut für Pharmakologie (R.R.), Universität zu Köln, Köln, Germany. Dr Grohé is now at Medizinische Klinik II, Universität Bonn, Bonn, Germany. Dr van Eickels is now at Molecular Cardiology Research Institute, Tufts University, Boston, Mass.
Correspondence to Dr Georg Nickenig, Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, 66421 Homburg/Saar, Germany. E-mail Nickenig{at}med-in.uni-sb.de
Background—Postmenopausal estrogen deficiency is associated with an increased cardiovascular risk, hypertension, and oxidative stress. Angiotensin type 1 (AT1) receptor regulation is involved in the pathogenesis of atherosclerosis. To characterize vascular function, oxidative stress, and AT1 receptor regulation during estrogen deficiency, ovariectomized spontaneously hypertensive rats (SHR) were investigated in comparison with sham-operated animals and with ovariectomized rats receiving estrogen replacement therapy with 17ß-estradiol.
Methods and Results—Arterial blood pressure was similar in all 3 groups investigated. Five weeks after ovariectomy, endothelial dysfunction in aortic rings was observed, which was reversed by estrogen replacement therapy. Estrogen deficiency led to an enhanced vasoconstriction by angiotensin II. Vascular superoxide production was significantly increased compared with that in sham-operated rats, as measured by lucigenin chemiluminescence assays. Estrogen substitution normalized the production of free radicals in the vessel wall. Vascular AT1 receptor expression was significantly upregulated by estrogen deficiency, as shown by quantitative reverse transcription–polymerase chain reaction, whereas endothelial NO synthase mRNA expression and NO release were unchanged. Five-week treatment of the animals with the AT1 receptor antagonist irbesartan prevented endothelial dysfunction in ovariectomized rats and normalized the vascular production of free radicals.
Conclusions—In SHR, estrogen deficiency leads to increased vascular free radical production and enhanced angiotensin II–induced vasoconstriction via increased vascular AT1 receptor expression, resulting in endothelial dysfunction. Estrogen replacement therapy and AT1 receptor antagonism prevent these pathological changes. Therefore, estrogen deficiency–induced AT1 receptor overexpression and oxidative stress may play an important role in cardiovascular diseases associated with menopause.
Key Words: angiotensin • atherosclerosis • hormones • endothelium
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